doi: 10.1111/j.1365-2222.2008.03134.

Clinical and Experimental Allergy, 39, 2032

c 2008 The Authors c 2008 Blackwell Publishing Ltd Journal compilation

REVIEW

Do helminth parasites protect against atopy and allergic disease?

C. Flohr, R. J. Quinnellw and J. Brittonz
Institute of Clinical Research and Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK, wInstitute of Integrative and Comparative

Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK and zDivision of Epidemiology and Public Health, University of Nottingham, Nottingham, UK

Clinical and Experimental Allergy

Correspondence: Dr Carsten Flohr, Institute of Clinical Research and Centre of Evidence Based Dermatology, University of Nottingham, Nottingham NG7 2UH, UK. E-mail: carsten.ohr@nottingham.ac.uk Cite this as: C. Flohr, R. J. Quinnell and J. Britton, Clinical and Experimental Allergy, 2009 (39) 2032.

Summary Allergic diseases are rare in areas with high helminth parasite exposure and common where helminth exposure is lacking or signicantly reduced, such as urban areas of developing countries and industrialized nations. Studies suggest that helminths induce a systemic immuno-modulatory network, including regulatory T cells and anti-inammatory IL-10, which might play a key role in the protection against the allergic phenotype. Here, we review the current cross-sectional, birth cohort, and intervention study evidence for a protective effect of helminth infection on allergy. There is increasing evidence for a causal relationship between helminth infection and reduced skin prick test responsiveness to allergens. Cross-sectional studies have shown a consistent negative relationship, and these results have been conrmed in several, although not all, intervention studies. The immunological basis for this protective effect is less clear. Recent studies do not support the mast-cell IgE saturation hypothesis, but suggest that protection is associated with IL-10 production. As for allergic disease, cross-sectional studies support a negative relationship between clinical asthma and infection with some helminth species, particularly hookworm, but more studies are required to draw conclusions for eczema and rhinitis. In addition, none of the few intervention studies to date have demonstrated an increase in clinical allergy after helminth treatment, and further studies are needed. Furthermore, we are only beginning to understand the host genetic factors that are potentially involved. A genetically predetermined T-helper type 2 cell-dominated cytokine milieu reduces parasite burden and may enhance host survival in an environment where helminth parasites are prevalent. Lack of parasite exposure in such hosts might lead to hypersensitivity to seemingly minor environmental allergen stimuli. Large birth cohort studies in helminth-endemic areas that use epidemiological, genetic, and immunological tools are required to further examine how helminth parasites affect the development of atopy ve allergic and allergic disease. Intervention studies with hookworm in parasite-na individuals are currently ongoing in the United Kingdom to test the above hypotheses further.

Introduction About one in ve children in industrialized countries suffer from asthma, allergic rhinitis (AR), or eczema, the so-called allergic diseases [1]. A positive family history is a strong risk factor for allergic disease susceptibility. However, genetic factors cannot explain the marked increase in allergic disease prevalence that has occurred in many economically developed countries over recent decades, the urbanrural prevalence gradient in less developed countries, the strong social class gradient in disease risk [24], or that migrants tend to acquire the allergy risk of their host population [57]. Epidemiological research has therefore focused on identifying the

possible environmental factors that are associated with increased allergy risk, with a particular emphasis on investigating lifestyle differences and other exposures that might be responsible. Helminth infections are one of the factors identied in this context. World-wide, more than two billion people are chronically infected with soil-transmitted helminths (STH): schistosomiasis, Ascaris lumbricoides, the hookworms (Ancylostoma duodenale and Necator americanus), and Trichuris trichiura [8]. Poor sanitation and hygiene are the main factors that predispose to all four infections. While Ascaris and Trichuris are transmitted fecal-orally, hookworm larvae and schistosomal cercariae enter the host via the skin. All these infections, with the exception

Do helminth parasites protect against atopy and allergic disease?

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of Trichuris, have a systemic phase in the lifecycle, which requires the parasite to survive in the bloodstream and selected internal organs of the host. Another potentially important group of helminth parasites with regard to allergic diseases are larial nematodes, principally Wuchereria bancrofti, Brugia malayi, and Onchocerca volvulus, and around 150 million people are thought to be infected world-wide [9]. Filarial infections are characterized by long-lived, tissue-dwelling adult worms, with transmission by blood-feeding insects. In endemic areas without existing de-worming campaigns, people are commonly chronically infected with multiple helminth species. Immune responses in helminth infections and allergy share many important features, such as a T-helper type 2 (Th2)-dominated cytokine milieu, associated with an upregulation of IL-4-, IL-5-, and IL-13-mediated IgE and mast cell production as well as eosinophilia (Fig. 1). Such Th2 responses are generally protective against parasitic infection, although IgE-driven acute sequelae of helminth infection, for example eosinophilic pneumonitis associated with ascariasis, are occasional disease complications [10, 11]. Indeed, it is generally considered that Th2 responses evolved to control extra-cellular parasites. Because this Th-2-mediated immunity is also central to the pathogenesis of allergic disease, it may be that susceptibility to allergic disease in developed countries represents the manifestation of a phenotype with particularly strong Th2-driven responses, which originally conveyed a higher chance of survival in an environment
Helminth exposure + + IL-4, IL-5, IL-13 total IgE mast cell production eosinophilia + Risk of allergic disease + Increases Reduces Upregulation

Antenatal

Postnatal

rT cells IL-10 TGF- Helminths Allergy

Helminths

Maternal/ infant genetic factors

Immunological phenotypes Allergy

Helminths

Helminths Th2 IL-4, IL-5, IL-13

Fig. 2. Helminth exposure in endemic areas (green) occurs already in utero and continues post-natally. It is very likely that host genetic factors through interaction with helminth parasites determine the regulatory T cell-dominated immunological phenotype that is thought to underlie the observed decrease in allergy risk. In areas where helminth exposure is signicantly reduced or absent (red), a Th2-dominated cytokine milieu continues to evolve and leads to an increased risk in atopy and clinical allergy. r T cells, regulatory T cells; Th2, type 2 T helper cells.

Acute heminth infection

r T cells IL-10 TGF- Chronic helminth infection

where parasitic infestations were endemic. In the absence of endoparasite and other infective stimuli, however, it is possible that the immune system does not develop immune tolerance post-natally, and this may consequently lead to a pre-disposition to allergic disease ([12]; Fig. 2). While IgE-mediated host responses are associated with helminth infections, parasites have developed methods to modulate the host immune system, presumably to permit and prolong survival within the host [11]. Despite the immunological similarities between host responses to endoparasitic infections and to external allergens, helminth-infected individuals appear to be protected from mast cell degranulation and inammatory responses in affected tissues, and it has been suggested that this is due to a protective immuno-modulatory network generated by parasite-induced T cells and their cytokines, including IL-10, ultimately leading to prevention of allergic tissue inammation [11, 13, 14]. In this paper, we review recent studies of the interaction between helminth infection and allergic disease, concentrating on community-based studies in humans. Papers on the current epidemiological, immunological, and genetic evidence for a protective effect of helminthic infections on atopy and allergies were identied through searches of MedLine, EMBASE, Web of Science, and Biosis Reviews from their inception to the end of July 2008.

Fig. 1. Helminth infections and allergic diseases are strong inducers of Th2 responses. The up-regulation of IL-4, IL-5, IL-13, total IgE and eosinophilia are part of the host immune response against the parasite and are hallmarks of acute helminth infections as well as allergic disease. However, helminth infections tend to be long-lived and largely asymptomatic. There is evidence to suggest that helminth infections are sustained through a parasite-induced immuno-modulatory network, in particular activation of regulatory T cells and systemically elevated levels of IL-10 and possibly TGF-b. This, in turn, may have a down-regulatory effect on the risk of developing allergic disease. r T cells, regulatory T cells.
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Perinatal exposure to parasite antigens Fetal exposure to helminth antigens can occur in utero through maternal infection [15]. For instance, cord blood lymphocytes from babies born to helminth-infected mothers have been found to produce parasite antigenspecic IgE [16, 17]. Another source of helminth antigen exposure of the neonate may be through breastmilk as

The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

22 C. Flohr et al well as early post-natal infection, although the latter is probably less important in children who are not yet able to walk. It has also been suggested from work on lymphatic lariasis that such early exposure may lead to lasting immune tolerance to parasite antigens and may prevent children from developing tissue inammation in response to acute infection and re-infection, and that this may be particularly advantageous in highly endemic areas [15, 1820]. Thus, perinatal exposure to high levels of parasite antigen may prove sufcient to induce long-term immune system hyporesponsiveness, and through the crossreactivity between parasite antigens and environmental allergens, such as house dust mites (HDMs) and cockroach, this may also confer protection against atopy and allergic disease ([21]; Fig. 2). Helminths and skin sensitization to environmental allergens (atopy) Following the suggestion that frequent and heavy helminth infection might protect against allergic skin sensitization based on observations made among Venezuelan children [22], there have been a number of cross-sectional studies of the relationship between atopy and helminth infection, summarized in Table 1. Protective effects on skin prick test (SPT) responses have been consistently

Table 1. Cross-sectional studies on the link between helminths and skin prick test positivity (atopy) Type of helminth infection (author, country, year) Any helminth Cooper et al., Ecuador, 2003 [25] Cooper et al., Ecuador, 2003 [26] Cooper et al., Ecuador, 2004 [27] Davey et al., Ethiopia, 2005 [28] Flohr et al., Vietnam, 2006 [29] Nyan et al., The Gambia, 2001 [30] Hookworm Cooper et al., Ecuador, 2003 [25] Cooper et al., Ecuador, 2003 [26] Dagoye et al., Ethiopia, 2003 [24] Davey et al., Ethiopia, 2005 [28] Flohr et al., Vietnam, 2006 [29] Grove & Forbes, Papua New Guinea, 1975 [31] Scrivener et al., Ethiopia, 2001 [32] Ascaris Cooper et al., Ecuador, 2003 [25] Cooper et al., Ecuador, 2003 [26] Dagoye et al., Ethiopia, 2003 [24] Flohr et al., Vietnam, 2006 [29] Obihara et al., South Africa, 2006 [33] Palmer et al., China, 2002 [23] Scrivener et al., Ethiopia, 2001 [32] Trichuris Cooper et al., Ecuador, 2003 [25] Cooper et al., Ecuador, 2003 [26] Dagoye et al., Ethiopia, 2003 [24] Scrivener et al., Ethiopia, 2001 [32] Schistosomiasis Araujo et al., Brazil, 2000 [34] van den Biggelaar et al., Gabon, 2000 [35] Number of participants 4433 2865 1002 7649 1742 429 4433 2865 7155 7649 1742 50 atopics 139 non-atopics 403 4433 2865 7155 1742 359 1896 403 4433 2865 7155 403 42 cases 133 controls 520

Age 518 519 717 5701 618 1534 518 519 14 5701 618 All ages 14601 518 519 14 618 614 818 14601 518 519 14 14601 640 514

Odds ratio (95% CI) 0.62 (0.500.76) 0.64 (0.520.78) 0.65 (0.470.91) 0.75 (0.580.97) 0.70 (0.500.99) 0.30 (0.110.80) 0.67 (0.331.37) 0.39 (0.180.85) 1.20 (0.701.70) Dp 1.30 (0.802.20) Cock 0.74 (0.550.99) 0.61 (0.390.96) 0.24 (0.110.51) 1.70 (0.883.27) 0.65 (0.540.78) 0.74 (0.600.91) 1.10 (0.702.00) Dp 1.00 (0.701.40) Cock 0.28 (0.100.78) 0.57 (0.231.40) Increased no of pos SPTs 1.52 (0.812.87) 0.69 (0.560.86) 0.82 (0.671.01) 1.40 (0.902.20) Dp 1.70 (1.102.40) Cock 1.10 (0.562.16) 0.14 (0.030.63) 0.32 (0.160.63)

Effect direction k k k k k k NS k NS NS k k k NS k k NS NS k NS " NS k Borderline k NS " NS k k

Calculated from raw data as protective effect of 42000 epg. Calculated from raw data.

k, negative association between helminths and atopy; " , positive association between helminths and atopy; NS, non-signicant; SPT, skin prick test; CI, condence interval.
c 2008 The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

Do helminth parasites protect against atopy and allergic disease?

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shown for all helminths investigated, including A. lumbricoides, T. trichiura, hookworm, and Schistosoma, although the effect sizes have been varied and have not always been statistically signicant. Although the number of studies is small, schistosome infection appears to have the strongest protective effect. In contrast, in the case of Trichuris and Ascaris infection, one study for each parasite has found a signicant increase (rather than decrease) in atopy risk [23, 24]. To our knowledge, there have been no published studies on the relationship between larial infection and atopy. Helminths and clinical allergic disease While the majority of studies point towards an inverse relationship between SPT positivity and helminth infection, the picture is less clear for clinical allergic disease, namely asthma, eczema, and hayfever. Hayfever In 1976, a British researcher reported having been completely symptom free from hitherto treatment-resistant hayfever, while he remained experimentally infected with N. americanus [36]. However, few have studied the association between hayfever and helminths since. Lynch et al. looked at urbanrural prevalence differences of allergic disease and helminth infection among 811 Venezuelan children. AR was signicantly more common in the urban population while A. lumbricoides was equally prevalent among both urban and rural participants [37], suggesting that other exposures were responsible for urbanrural prevalence differences in rhinitis. Equally, a large crosssectional questionnaire-based survey conducted in a paediatric population in rural Ecuador found no signicant association between rhino-conjunctivitis symptoms and A. lumbricoides infection (adjusted odds ratio (OR) = 1.00, 0.551.79 [27]), nor did a population-based cross-sectional survey in Cape Town, South Africa (OR = 1.04, 0.224.82 [33]). However, a study conducted among 3,107 primary schoolchildren in Taipei, Taiwan, suggested that Enterobius vermicularis may be protective against physiciandiagnosed rhinitis (adjusted OR = 0.61, 0.450.84 [38]). Eczema There is evidence from observational studies that eczema is common in populations with a low parasite burden [12, 3942]. However, cross-sectional studies have not provided strong evidence for an effect of helminth infection on eczema, with both negative and positive associations reported. In 2005, Sch afer et al. [43] showed an independent inverse association between A. lumbricoides and questionnaire-diagnosed eczema in a population-based study of 4169 East German children (adjusted OR = 0.45,
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0.330.60). This effect was even more pronounced in children with increased specic IgE levels to aeroallergens (adjusted OR = 0.31, 0.180.56), suggesting that helminth infection may be causing a dissociation between sensitization and eczema phenotype. The latter has also been observed in other developing country settings [44]. Further supporting evidence for an inverse relationship between eczema and helminth infection comes from a small birth cohort study among 103 motherinfant pairs in Uganda, where cumulative eczema risk was decreased by 74% until age 15 months among children whose mothers were infected with helminths (predominantly hookworm) during the last trimester of pregnancy (adjusted OR = 0.26, 0.080.83 [45]). In contrast, a nested casecontrol study among 732 Ethiopian children age 15 indicated a signicant positive association between exural eczema and the presence of any parasite infection, with this effect predominantly caused by Trichuris, but not Ascaris or hookworm (adjusted OR Trichuris = 1.61, 1.142.26 [46]). Finally, no signicant association was seen with Ascaris or Trichuris infection in a cross-sectional survey among 4433 Ecuadorian schoolchildren (adjusted OR = 0.85, 0.501.46 [25]), nor with E. vermicularis infection among 3107 Taiwanese primary schoolchildren [38]. Asthma/wheeze Herrick [47] was the rst to recognize that helminths can trigger asthma attacks. Following his work in the early 20th century, little attention was paid to the potential links between endoparasitic infestations and asthma until the early 1970s. Reports that asthma was commonly caused by endoparasites were, however, not conrmed [48, 49]. Two previous reviews of the literature suggested that further evidence was needed to either support or disprove the hypothesis that parasites protect against asthma [50, 51]. A more recent systematic review and meta-analysis of 30 cross-sectional studies found that an inverse relationship between asthma and geohelminths was seen for hookworm infection (predominantly N. americanus; pooled OR = 0.50, 0.280.90), and that this effect was infection intensity related (OR for the highest tertile of infection intensity = 0.34, 0.190.62). However, A. lumbricoides appeared to increase asthma risk (pooled OR = 1.34, 1.051.71), while T. trichiura had no signicant effect (pooled OR = 1.19, 0.981.43; Fig. 3, [52]). In addition, one small population-based casecontrol study from Brazil has suggested that asthmatics infected with Schistosoma mansoni have a milder course of disease than non-infected individuals, marked by lower symptom frequency and reduced use of asthma medication. However, there was no difference in objective pulmonary function measurements between infected and non-infected asthmatics [53].

The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

24 C. Flohr et al
(a)
Parasites and asthma 06 Unadjusted and adjusted analyses asthma 01 Ascaris lumbricoides Odds ratio (random) 95% CI Odds ratio (random) 95% CI 1.14 0.27 29.46 0.72 0.78 1.46 4.10 1.74 472.01 0.88 1.62 [0.72, 1.80] [0.02, 3.06] [1.72, 504.21] [0.15, 3.40] [0.26, 2.33] [0.78, 2.74] [1.54, 10.90] [1.09, 2.78] [27.31, 8158.27] [0.55, 1.42] [0.95, 2.78]

Study or sub-category

01 Unadjusted analyses Aderele Alcasid Alshistawy Carswell 1976 Carswell 1977 Cheah Kayhan Salako Tullis Wolstenholme Subtotal (95% CI) Test for heterogeneity: = 33.75, DF = 9 (P < 0.0001), I = 73.3% Test for overall effect: Z = 1.77 (P = 0.08) 02 Adjusted analyses Bencio Calvert Cooper Dagoye Davey Lynch Muniz Nascimento Palmer Scrivener Subtotal (95% CI) Test for heterogeneity: = 39.04, DF = 9 (P < 0.0001), I = 76.9% Test for overall effect: Z = 1.62 (P = 0.11) Total (95% CI) Test for heterogeneity: = 72.84, DF = 19 (P < 0.00001), I = 73.9% Test for overall effect: Z = 2.35 (P = 0.02) 0.01 0.1 1 10 100 Reduce asthma risk Increase asthma risk

2.66 1.75 1.39 0.39 1.04 1.22 2.49 1.11 2.26 0.70 1.26

[1.35, [1.17, [1.13, [0.20, [0.59, [0.86, [0.43, [0.82, [1.58, [0.46, [0.95,

5.21] 2.61] 1.71] 0.76] 1.81] 1.73] 14.53] 1.50] 3.23] 1.07] 1.66]

1.34 [1.05, 1.71]

(b)

Parasites and asthma 06 Unadjusted and adjusted analy ses asthma 02 Hookworm Odds ratio (random) 95% CI Odds ratio (random) 95% CI

Study or sub-category

01 Unadjusted analy ses Alshistawy Carswell 1976 Carswell 1977 Cheah Salako Tullis Subtotal (95% CI) Test f or heterogeneity : = 21.56, DF = 5 (P = 0.0006), I = 76.8% Test f or ov erall ef f ect: Z = 0.76 (P = 0.45) 02 Adjusted analy ses Dagoy e Dav ey Scriv ener Subtotal (95% CI) Test f or heterogeneity : = 2.63, DF = 2 (P = 0.27), I = 23.9% Test f or ov erall ef f ect: Z = 3.72 (P = 0.0002) Total (95% CI) Test f or heterogeneity : = 24.55, DF = 8 (P = 0.002), I = 67.4% Test f or ov erall ef f ect: Z = 2.29 (P = 0.02) 0.1 0.2 0.5 1 2 5 10

1.66 1.15 0.44 1.68 0.21 0.41 0.67

[0.17, [0.21, [0.12, [0.77, [0.12, [0.02, [0.23,

16.56] 6.32] 1.66] 3.65] 0.35] 9.44] 1.90]

0.27 0.57 0.28 0.37

[0.06, [0.29, [0.15, [0.22,

1.10] 1.10] 0.52] 0.63]

0.50 [0.28, 0.90]

Reduce asthma risk

Increase asthma risk

Fig. 3. Relationship between Ascaris lumbricoides (a), hookworm (b), and Trichuris trichiura (c) infection and asthma in cross-sectional studies, using meta-analysis. Results are presented as odds ratios for individual studies (squares) and in pooled analysis (rhomboids), using random effect models. Reproduced with permission from the Am J Respir Crit Care Med [52].
c 2008 The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

Do helminth parasites protect against atopy and allergic disease?

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(c)

Parasites and asthma 06 Unadjusted and adjusted analyses asthma 03 Trichuris trichuria Odds ratio (random) 95% CI Odds ratio (random) 95% CI
1.35 0.86 1.69 0.20 1.31 1.27 [0.78, [0.32, [0.92, [0.03, [0.79, [0.90, 2.33] 2.34] 3.10] 1.40] 2.17] 1.79]

Study or sub-category
01 Unadjusted analyses Aderele Alcasid Joubert Klein Wolstenholme

Subtotal (95% CI) Test for heterogeneity: = 4.95, DF = 4 (P = 0.29), I = 19.1% Test for overall effect: Z = 1.34 (P = 0.18) 02 Adjusted analyses Bencio Cooper Dagoye Davey Lynch Muniz Nascimento Scrivener Subtotal (95% CI) Test for heterogeneity: = 13.17, DF = 7 (P = 0.07), I = 46.8% Test for overall effect: Z = 1.29 (P = 0.20) Total (95% CI) Test for heterogeneity: = 18.95, DF = 12 (P = 0.09), I = 36.7% Test for overall effect: Z = 1.79 (P = 0.07) 0.01 0.1 1 10 100 Reduce asthma risk Increase asthma risk

8.32 1.04 0.90 1.30 1.17 2.70 1.19 0.97 1.17

[2.48, [0.85, [0.53, [0.40, [0.82, [0.42, [0.87, [0.64, [0.92,

27.95] 1.28] 1.54] 4.17] 1.69] 17.27] 1.63] 1.49] 1.47]

1.19 [0.98, 1.43]

Fig. 3. Continued.

Evidence from intervention studies Despite mounting cross-sectional evidence that STHs are associated with protection against SPT positivity to aeroallergens, asthma, and potentially eczema, this observation does not prove causality. Confounding by other exposures remains a clear possibility, as does reverse causation arising from higher levels of protection from helminth infection among allergic individuals. To address these possibilities, evidence is required on the effects of either parasite infection in previously unexposed allergic individuals, or of the effect of parasite eradication on allergic disease prevalence in helminth-infected populations. In the latter group, two studies in children, one an observational study built into a helminth eradication programme in 375 Venezuelan children [54], the other a single blind trial of 317 children in Gabon [55], have reported evidence of a signicant increase in allergic skin sensitization following anti-helminthic therapy, consistent with the hypothesis that helminth parasites protect against atopy. We have also recently completed an individually randomized placebo-controlled trial among 1566 Vietnamese schoolchildren and shown a signicantly higher risk of allergic sensitization in the antihelminthic treatment compared with the placebo group after 12 months (adjusted OR = 1.31, 1.021.67), and this effect was particularly strong in children infected with
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both Ascaris and hookworm at baseline (adjusted OR = 4.90, 1.4816.19 [56]). However, no effect of deworming treatment on atopy was shown in a cluster randomized trial of helminth therapy in 2372 Ecuadorian children [57]. There is no evidence to date for an increase in clinical asthma after anti-helminthic treatment, as neither our study in Vietnam nor the Ecuadorian study found a signicant effect [56, 57]. However, a randomized placebo-controlled study in Uganda among 103 motherinfant pairs found that administration of albendazole to pregnant mothers was associated with an increased cumulative eczema risk in infants until age 15 months in univariate analysis [45]. This effect did not reach statistical signicance after adjustment for potential confounders (adjusted RR = 2.40, 0.777.48), possibly due to small participant numbers and resulting low statistical power. In contrast, clinical improvement of established asthma following de-worming was reported in a small study among 89 Venezuelan adults and children with asthma. In the same individuals, a reduction in positive SPT responses and specic IgE levels to HDM was also seen [58]. As far as we are aware, there are to date no published studies of the effects of parasite infection in previously uninfected individuals with allergies. J. B., in collaboration with Prof. David Pritchard (University of Nottingham), has recently initiated studies of hookworm (N. americanus) as

The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

26 C. Flohr et al a potential therapeutic agent for allergic disease [59]. A safety study of the effect of hookworm infection on airway responsiveness in individuals with AR has been conducted (http://clinicaltrials.gov/ct2/show/NCT00232518; paper submitted for publication), and an intervention trial in asthmatics is currently being completed (http://clinical trials.gov/ct2/show/NCT00469989). The immuno-epidemiology of allergy and atopy in helminth-infected populations For at least some helminth species, the epidemiological evidence reviewed above suggests that parasite infection is associated with lowered SPT responses to allergen and lowered risk of clinical asthma. Several immunological mechanisms have been suggested to explain the potential anti-allergy effects of helminths (reviewed by [13, 6062]). Up-regulated Th2 responses in helminth-infected individuals may interfere with anti-allergen effector pathways either directly via antibody-mediated interactions at the mast cell surface (the IgE saturation hypothesis). Alternatively, the induction of an anti-inammatory network mediated by dendritic cell and regulatory T cells may suppress immune responses to both helminth and nonhelminth antigens. These mechanisms are not mutually exclusive, as key anti-inammatory molecules such as IL-10 also affect antibody production. There may also be direct effects of parasite products, for instance mast cell degranulation is inhibited by the larial parasite product ES-62 [63]. Here, we concentrate on evidence from recent human eld studies and propose that convincing evidence for a role of immune responses in mediating the protective effects of helminth infection on allergic disease and atopy requires that the immune response meets the following criteria: rstly, it should be negatively associated with allergy in parasitized populations, not only in cross-sectional analysis but also longitudinally after treatment. Secondly, the immune response should be up-regulated in helminth infection, and decrease after helminth treatment. Mast cell immunoglobulin E receptor saturation hypothesis The IgE saturation hypothesis was the earliest suggested mechanism to potentially explain a protective effect of helminth parasites on allergic disease [64, 65]. It was based on the observation that helminth infections stimulate polyclonal total IgE production, often to a much greater level than seen in unparasitized individuals with either asthma or eczema, suggesting that high levels of polyclonal IgE could saturate IgE receptors on the mast cell surface, preventing binding of allergen-specic IgE and mast cell degranulation. In addition, total IgE levels typically decrease after anti-helminthic treatment [54, 55, 58]. Further supporting evidence also came from in vitro studies, which suggested that inhibition of mast cell histamine release was possible in the presence of high total IgE levels [65]. This hypothesis predicts that total IgE levels or the ratio of total : allergen-specic IgE are critical for helminth-mediated protective effects on allergic disease phenotypes. Two recent studies in humans have tested the IgE saturation hypothesis, demonstrating that basophils from hookworm or larial patients with high levels of polyclonal IgE retain the ability to release histamine in response to parasite antigens in vitro [66, 67]. Moreover, in larial patients there was no change in histamine release over a wide range of natural ratios of polyclonal to specic IgE, from 14 : 1 to 388 : 1, likely related to the IgE-driven increased FceRI expression on basophils. However, higher ratios of 4500 : 1 did block histamine release in vitro. The authors suggest that such ratios are unlikely to be seen in human helminth infections, and further studies of total : anti-allergen IgE ratios would be useful to conrm this. Human eld studies that have measured total IgE levels and their relation to SPT positivity and/or clinical allergy have also not shown a convincing inverse relationship (Table 2). It is possible that these results are confounded by variation in the ratio of total : allergen-specic IgE, and few studies have measured this ratio. The effects of helminth infection on specic (anti-allergen) IgE are apparently variable, as intervention studies have shown no change [55, 56], an increase [54], or a decrease [58] in specic IgE after anti-helminthic treatment. It has also been suggested that effects vary with the intensity of infection, with low-intensity infection stimulating specic IgE and thus SPT responses and suppression only seen in high-intensity infection [37]. However, an inverse relationship between helminth infection and atopy has been shown in low-intensity infection areas as well [29]. In summary, both the immuno-epidemiological and the experimental evidence suggests that the IgE saturation hypothesis is unlikely to explain reduced SPT responses in helminth-infected populations, except perhaps in a very small number of individuals [66, 67, 79]. However, further studies of basophil responses to non-helminth allergens, and of total : specic IgE ratios in other helminth infections, such as Ascaris infection, would be useful. Other potential antibody-mediated mechanisms have been proposed, such as the production of low-afnity antiallergen IgE, or blocking by anti-allergen IgG4, but both have so far received little attention [13, 80]. Anti-inammatory regulatory network Human and murine studies have revealed that helminth infection induces a complex immuno-regulatory network. This includes dendritic cells, natural regulatory T cells,

c 2008 The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

Do helminth parasites protect against atopy and allergic disease? Table 2. Evidence for a protective effect of helminth-induced immune responses on atopy and allergy Prediction Association with atopy Total IgE Negative (high IgE, low atopy risk) Cooper et al. 2003 [26] Hagel et al. 1993 [68] Van den Biggelaar et al. 2001 [69] No association Lynch et al. 1987 [70] Scrivener et al. 2001 [32] Van den Biggelaar et al. 2004 [55] Positive (high IgE, high atopy risk) Flohr et al. 2007 [56] Grove et al. 1974 [72] Lynch et al. 1987 [70] Nyan et al. 2001 [30] Negative (high IgE, low asthma risk) Warrell et al. 1975 [73] No association Carswell et al. 1977 [74] Medeiros et al. 2003 [53] Scrivener et al. 2001 [32] Selassie et al. 2000 [75] Positive (high IgE, high asthma risk) Alshishtawy et al. 1991 [76] Palmer et al. 2002 [23] Macfarlane et al. 1979 [77] No studies. No studies. Yes Van den Biggelaar et al. 2004 [55] Lynch et al. 1993 [54] Lynch et al. 1997 [58] No Flohr et al. 2007 (non-signicant reduction) [56] Not measured Araujo et al. 2004 [78] IL-10 Negative (high IL-10, low atopy risk) Flohr et al. 2007 (hookworm-induced IL-10) [56] Van den Biggelaar et al. 2000 (schistosome-induced IL-10) [35]

27

No association Cooper et al. 2008 (Ascaris-induced IL-10, allergen-induced IL-10) [71]

Positive (high IL-10, high atopy risk) No studies.

Association with allergy Asthma/wheeze

Negative (high IL-10, low asthma risk) No studies. No association No studies.

Positive (high IL-10, high asthma risk) No studies.

Eczema Hayfever Intervention studies Decrease after helminth treatment

No studies. No studies. Yes Araujo et al. 2004 (house dust mite-induced IL-10) [78]

No Flohr et al. 2007 (non-signicant reduction hookworm-induced IL-10) [56] Not measured Lynch et al. 1993 [54] Lynch et al. 1997 [58] Van den Biggelaar et al. 2004 [55]

inducible regulatory T cells (Tr1 cells), and alternated activated macrophages [81]. There are a number of potential immunosuppressive mechanisms associated with these subsets, but production of the anti-inammatory cytokines TGF-b and especially IL-10 is thought to play a key role. A number of murine studies have demonstrated helminth-induced down-regulation of allergic responses, with evidence for both IL-10-dependent and non-IL-10dependent mechanisms [8286]. However, it should be noted that parasite-induced exacerbation of allergic tissue inammation has also been observed in some murine models [62, 82]. Human eld studies of asthma and helminths have focused on one potential immunosuppressive marker,
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IL-10. Up-regulation of IL-10 production in helminth infection has been shown for larial and schistosome infections [8790]. However, evidence for up-regulated IL-10 production in hookworm [9193] and Ascaris [71, 9497] infection is less consistent, although a signicant decline in IL-10 production after treatment of hookworm infections has been seen [93]. Two studies have shown a negative relationship between anti-parasite IL-10 production and SPT responses in hookworm and schistosome infection in cross-sectional analysis ([35, 56]; Table 2). The hookworm study also assessed cytokine levels after anti-helminthic therapy with a nonsignicant decline in IL-10 [56]. In addition, a case control study among helminth-infected and non-infected

The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

28 C. Flohr et al asthmatics demonstrated a positive association between schistosome infection status and HDM-induced IL-10 [78]. In this study, IL-10 levels also declined following antihelminthic therapy. However, a recent detailed study in an Ecuadorian population infected with Ascaris and Trichuris found no association between SPT responses and either anti-Ascaris or anti-allergen IL-10 production, and also no association with numbers of IL-10-positive T cells, including CD41CD251 subsets [71]. IL-10 may have a direct role in suppressing mast cell responses in helminth infection, as IL-10 suppression of mast cell histamine release has been seen in vitro [98]. An indirect role for IL-10 via the up-regulation of potentially blocking IgG4 responses has also been suggested [13]. Alternatively, IL-10 may be acting as a marker for the immunoregulatory response, or the relationship may be confounded by non-immunological factors [71]. Given the range of immuno-regulatory cells and mechanisms potentially involved, including IL-10 independent mechanisms [86, 99], there is a clear need for further longitudinal studies that measure not only SPT positivity in relation to IL-10 but also clinical allergy as well as other suppressive cytokines, such as TGF-b, and regulatory T cell subsets. Does atopy protect against helminth infection? Reverse causation and host genetics An alternative explanation for a negative association between helminths and atopy is that atopic individuals have a greater resistance to helminth infection. Indeed, this was the interpretation of the rst study to show such a negative association [31]. The immunological bias in atopic individuals may lead to stronger anti-parasite immune responses and thus lower parasite burdens. Evidence for stronger anti-parasite immune responses in atopics comes from a recent study by Cooper et al. [100] in which atopic children had stronger Th2 responses to Ascaris than non-atopics, with higher frequencies of IL-4and IL-5-expressing peripheral blood mononuclear cells and greater basophil histamine release in response to Ascaris antigen. These responses are potentially protective against helminth infection. However, anti-parasite IgE, which has also been associated with protection, is not consistently higher in atopics [32, 33, 56, 71]. Why might atopics be protected against parasites? Both atopy and helminth burden are known to have a signicant host genetic component [101, 102], and it has been hypothesized that both phenotypes are under common genetic control. This would provide an evolutionary explanation for genetic predisposition to atopy and allergy, as such individuals would be protected against helminth infection, and a functional explanation for the negative association between asthma and helminth burden. It has also been suggested that geographical variation in selective pressures for an up-regulation of Th2 responses may underlie some ethnic differences in allergy risk [103]. There is some indirect evidence that the same genes control atopy and helminth infection from work in different populations [104]. For instance, the Th2 gene cluster on chromosome 5q3133 has been linked to control of both asthma and schistosome phenotypes [105, 106]. Several association studies have demonstrated that risk alleles or haplotypes at asthma loci are associated with low worm burden. In particular, the study of STAT6 haplotypes in British asthmatics and Chinese with Ascaris infection has revealed that haplotypes associated with allergic phenotypes in the United Kingdom are associated with low Ascaris burden in China [107]. Similarly, the IL13-1055T allele has been associated with both low schistosome burden in Mali and an increased asthma risk in Europe [108, 109], and the ADRB2 Gly16 allele has been associated with low Ascaris burden in Venezuela and more severe asthma [110, 111]. Helminth-mediated immunomodulation may also be affected by host genetics, as IL-10 polymorphisms have been associated with SPT positivity and IL-10 production in children in Gabon [112]. These results are intriguing, although several caveats should be borne in mind. Very few genetic association studies have been performed for helminth infection, and associations require conrmation in independent populations. The loci investigated in helminth infection have been strongly biased towards loci known to be important in asthma. In contrast, loci identied from whole-genome scans for Ascaris and Trichuris infection, where loci are not selected a priori, did not contain genes known to be important in asthma [113, 114]. What is now required are genetic studies of allergic disease and helminth infection in the same population. In particular, pedigree-based genetic epidemiology studies have the potential to determine whether there is a positive genetic correlation between atopy, clinical allergy, and resistance to helminth infection across individuals, reecting common genetic control. Interestingly, a Venezuelan founder population with a genetic predisposition to asthma had lower Ascaris burdens than similar areas in Venezuela, although confounding effects cannot be ruled out [42]. Are all worms equal? The studies of interactions between helminths, allergy, and immune responses reviewed above show variable results, with both positive and negative associations reported. A possible explanation for this heterogeneity is variation between studies in the species of helminth, the age when infections were acquired, and the intensity of infection. Helminths are often implicitly treated as a homogeneous group, because they share a pronounced up-regulation of IgE responses, but important interspecies differences exist. In particular, the degree of

c 2008 The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation

Do helminth parasites protect against atopy and allergic disease?

29

immunosuppression induced by different species is likely to vary, with long-lived, tissue-dwelling parasites such as larial worms and schistosomes expected to induce stronger immuno-regulatory responses than lumen-dwelling gastrointestinal parasites [81]. It has also been suggested that parasites with a lung-migratory stage, such as hookworm, Ascaris, and schistosomes, may be more effective at suppressing allergic inammation in the lungs [32, 62]. There is some evidence from human eld studies for species differences in effects on allergy, although in most studies polyparasitism is common. The strongest associations between infection and atopy or asthma are seen for schistosome and hookworm infection, and there is evidence for a role of IL-10 in both infections. In contrast, Ascaris infection does not appear to protect against asthma, despite a lung-migratory stage, nor elicit a strong IL-10 response. Allergic reactions to parasite antigens are also more common in Ascaris infection. Furthermore, the degree of parasite-induced host immuno-suppression is likely to be positively associated with worm burden, as indicated by a lower atopy and asthma risk with higher helminth egg counts [26, 29, 32], and polyparasitism [29, 56]. Conclusions There is epidemiological evidence from a number of crosssectional and intervention studies to suggest a direct immuno-modulatory effect of helminth infection on SPT responses for hookworm, Ascaris, and schistosomes. To date, there have been no human studies with larial worms and this warrants further research. There is also cross-sectional evidence to suggest a protective effect of hookworm, but an exacerbatory effect of Ascaris infection, on asthma. However, two recent intervention studies have not demonstrated changes in asthma prevalence after helminth treatment. Thus, it is not possible to rule out that the cross-sectional associations with asthma result from confounding or reverse causation (e.g. host genetics). Cross-sectional studies on eczema and rhinitis are few in number and inconsistent. While the mast cell saturation hypothesis appears not to be important, there is limited evidence that helminth effects on atopy may be mediated by parasite-induced anti-inammatory IL-10. However, further detailed immunological studies are needed, and the precise mechanisms whereby intestinal or systemic helminths prevent mast-cell degranulation in the skin remain to be determined. It is likely that the perinatal environment plays an important role in the priming of the infants immune system. Large intervention and birth cohort studies that combine epidemiological, genetic, and immunological tools are required to shed further light on the intricate relationship between helminth infection and allergy. Of particular interest are geneenvironment interactions and regulatory T cell
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subsets and their cytokines as well as allergen-specic IgG4. It is hoped that such research, together with the currently ongoing intervention studies involving the voluntary infection of allergic individuals with helminth parasites, will ultimately lead to the development of parasite-derived drugs not only for the treatment but also for the prevention of allergic diseases.

Acknowledgements Conict of interest: None

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c 2008 The Authors c 2008 Blackwell Publishing Ltd, Clinical and Experimental Allergy, 39 : 2032 Journal compilation